In 1982 physicians first became aware of a new sexually transmitted disease that was associated with an unusual form of cancer (Kaposi""s sarcoma) and a variety of unusual infections. The disease was named acquired immune deficiency syndrome (AIDS), since both these problems reflected a severe deficiency in the helper T cells of the immune system. A retrovirus, called human immunodeficiency virus (HIV), was found to be the causative agent of AIDS.
HIV is a member of a family of viruses called lentiviruses that are part of a large group of viruses known as the Retroviridae. Some of the other members of the group are the closely related simian, feline and bovine immunodeficiency viruses. This group of viruses displays a variety of common features.
The fact that HIV has an extreme tendency to mutate to forms that are resistant to existing antiviral therapies greatly complicates attempts to treat the infection with antiviral drugs. Most of the current research in AIDS is aimed at understanding the life cycle of HIV. AIDS research has been targeted towards inhibition of the virus at different stages of its life cycle.
The molecular target for HIV inhibitors can be broadly classified into the following classes: reverse transcriptase (RT) enzyme, protease enzyme, integrase enzyme, regulatory proteins, and zinc finger domains in the nucleocapsid p7 protein.
The normal flow of genetic information is from DNA to RNA to protein, and hence HIV, which is a retrovirus, must first convert its genomic RNA into a double-stranded DNA in order to start its replication cycle in the host cell. This conversion takes place in the host cell cytoplasm with the help of a viral enzyme called reverse transcriptase (RT) that catalyzes a series of biochemical reactions involved in this process. This makes reverse transcriptase (RT) enzyme an attractive target for HIV inhibitors. HIV RT inhibitors can be broadly classified into nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). The modes of action of these two classes of compounds are different in nature. The nucleoside HIV RT inhibitors are competitive inhibitors that to bind to the catalytic site of the enzyme, and their mode of action appears to be through their triphosphates (produced in the cytoplasm of the host cell) that act as RT enzyme inhibitors through incorporation and termination of the growing viral DNA chain. Common nucleoside RT inhibitors are AZT, ddC, ddI, d4T, 3TC, and Abacavir.
This invention deals with non-nucleoside RT inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are non-competitive inhibitors of the RT enzyme; they bind to an allosteric (regulatory) site with a degree of magnitude heretofore not yet observed and influence the RT catalytic site. Hence, they are also referred to as second-site RT inhibitors. In general, at micromolar concentrations NNRTIs inhibit HIV-1 in vitro with minimum or no cytotoxicity but do not inhibit HIV-2 or other retroviruses. Some non-nucleoside RT inhibitors are chloro-TIBO, nevirapine, L-697,661, and delavirdine.
1. Field of the Invention
The need and research for active inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is urgent and ongoing. In 1997, U.S. Pat. No. 5,608,085 issued to Baker et al. discloses a Synthesis of Optically Active Calanolides A and B and Enantiomers and Related Compounds, which produces anti-HIV-1 or HIV-2 compounds in high yields and in a high degree of purity. Recently, on Dec. 1, 1998, U.S. Pat. No. 5,843,990 issued to Baker et al. entitled Pyran-Chromenone Compounds, Their Synthesis and Anti-HIV Activity, which deals with a class of compounds, particularly optically active compounds of a high degree of purity and free of the corresponding enantiomers, which are highly potent anti-HIV compounds (Ref 25). In accordance with this invention, novel 2,3-dihydrobenzo[d]isothiazole 1,1-dioxides (sultams) have been discovered that are biologically active, particularly potent HIV reverse-transcriptase inhibitors. Further, a novel solid-phase combinatorial synthesis has been discovered in which a solid support is used.
Combinatorial organic synthesis (COS) is a known methodology for creating huge, searchable libraries of small organic molecules suitable for both drug-discovery screening and drug-development optimization. Frequently, the use of a solid support in the synthesis will usually eliminate the need for difficult-to-automate procedures like extractions, filtrations and chromatography. Multistep syntheses are typically carried out to completion without purification of the products at intermediate stages. Further, the use of a solid support facilitates the use of a split-pool technique, which offers the most efficient manner of synthesizing large libraries (103-109 compounds). Combinatorial chemistry processes commonly use automation which provides several advantages: First, automated systems perform functions that are impossible to do by hand, such as delivering exceedingly small volume of liquids to precise locations. Second, the consistency of an errorless process can be enhanced. Third, and perhaps more important, an appropriately designed automated system will perform functions quickly and repeatedly with consistency of quality and output over long periods of time.
The invention lends itself to the use of a solid support and of combinatorial synthesis.
2. Description of Related Art
Publications of interest relating to the subject matter of this invention include:
1. Borman, S., xe2x80x9cCombinatorial Chemistryxe2x80x9d, special report, CandEN News, page 47, Apr. 6, 1998.
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18. European patent application No. O 422 944 A1, published on Apr. 17, 1991, entitled Chiral Sultams. 
19. Snieckus, V., Chemical Synthesis: Gnosis to Prognosis, Chatagilialoglu, C.; Snieckus, V. Eds.; Kluwer Academic Publishers: Dordrecht, 1996, pp 191-221.
20. Alerton, E. et al., Proc. Am. Pept. Symp. pp 163-195. Pierce Chemical Company: Rockford, Ill. (1981).
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22. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley and Sons Inc.: New York, 1994.
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All references referred to in this text are incorporated herein by reference in their entirety.
The invention relates to a new class of compounds herein identified generally as sultams, which may be represented by the following formula VI, in which the numbering of the atoms is started with the sulfur atom of the isothiazole. Two of the rings (ring A and C) are aromatic, and the third is a heterocyclic ring (ring B), a cyclic sulfonamide. 
Sultams are derivates of isothiazole 1,1-dioxide (cyclic 5-membered sulfonamides) with an aromatic ring fused at the C-4 and C-5 positions of the isothiazole ring. The investigated sultams have various substituents on the aromatic rings. The nitrogen of the sulfonamide is either tertiary or secondary depending on the nature of the substituents on that atom. On the C-3 position of sultams a variety of aromatic substituents are possible depending whether aldehydes or ketones are used in the synthesis. The other substituents on the same carbon can either be hydrogen, when an aldehyde is the reactant, or another substituent defined further below. This carbon, which has four ligands, or three ligands and hydrogen, is asymmetric, and thus determines the chirality of the resulted sultams. A racemic substance comprised of a pair of enantiomers is generally the product of synthesis, which substance can be resolved into the respective enantiomers.
The invention provides several methods of synthesis of the compounds of the invention, in particular a synthesis which uses a solid phase (or support), which allows readily the construction of a combinatorial library. The invention also provides such a combinatorial synthesis that can be carried out by automation. Such solid-phase syntheses have been described in the review article by Corbett (ref 24).
Several difficulties were encountered when attempts were made to use methods available in the literature to make ring compounds in racemic form. Ultimately, a synthesis was developed in which the nitrogen atom of the compounds remains linked throughout the synthesis to a solid support until its removal concurrently with closure of ring B.
Synthesis variations are also taught by the invention that provide a variety of substituents on the rings of the compounds. One such synthesis yields compounds wherein RN is hydrogen. Another synthesis provided by the invention that does not need to use a solid support yields compounds in which all substituents R are hydrogens. Another synthesis variation provided by the invention that can be performed with or without a solid support, yields compounds wherein RQ is CF3. Other variations are described hereafter.
An objective of the synthesis was to obtain biologically active compounds, especially anti-HIV compounds. The sultam compounds of the invention offer the possibility of a variety of structural modifications and various possibilities of positioning of different substituents in different positions on any one of the rings. It was not known prior to this invention what effect these various substituents and their different positions on the nitrogen, on the stereogenic carbon, and on the ring(s) would have on their biological and more particularly their anti-HIV activity.
The invention also provides a new class of such compounds in racemic form that can be resolved into their respective enantiomers. A group of these compounds has an anti-HIV potency heretofore unachieved with this class of compound. In accordance with the invention, an area of the molecule has been identified on which appropriate substituents appear to make a major combination to a high degree of anti-HIV potency.
The invention also provides a method for alleviating, treating or preventing viral infections, especially strains of the HIV virus.
The invention also provides biologically active compositions which comprise one or more compounds of the invention, in an effective, nontoxic amount in combination with a biologically or pharmaceutically acceptable carrier.
The invention also provides drug combinations of compounds of the invention with HIV protease inhibitors, like ritonavir, saquinavir mesylate, and others.
In still another aspect, the invention provides a method for treating a mammal, particularly a human, infected with a retrovirus, which comprises administering to said mammal in need of such treatment an effective nontoxic amount of the composition(s) of the intention.
In summary, the invention contributes to solve a serious and urgent worldwide health need which has adverse social and economic consequences.